DESCRIPTION: (Principal Investigator's Abstract) With the advent of Lewis acid-mediated radical reactions, impressive advances have been made in the last five years in the control of acyclic stereochemistry using chiral auxiliaries. In contrast, enantioselective carbon-carbon bond construction using radical intermediates is still in its infancy. The design of chiral catalytic radical reactions for obtaining high stereoinduction is a challenge. We and others have investigated chiral Lewis acid-mediated enantioselective radical reactions. A few important advancements have been made in this regard in the previous grant period. This continuation (GM-54696) proposal outlines a mixture of new methodology development using free radicals along with application of the newly discovered methods to natural product synthesis. In this proposal we will specifically address: (a) The establishment of one, two, and three chiral centers with relative as well as absolute stereocontrol by intermolecular radical reactions in acyclic systems. The newly developed methodology will be applied to the total synthesis of antiallergenic neolignan magnosalicin, in the formal total synthesis of cytotoxic octalactin A and to the preparation of C-glycosides. (b) The construction of carbo- as well as heterocyclic compounds through intramolecular enantioselective radical cylizations. Processes in which two or more contiguous chiral centers are established will be explored. The application of the methodology to lactone natural products with biological activity will be undertaken. (c) Enantioselective radical annulation reactions will be investigated in detail. Specifically, the formation of medium size rings will be explored. The annulation methodology will constitute a key disconnection in our effort towards the total synthesis of structurally complex tetracyclic diterpenes, the asbestinins, which show promising cytotoxicity against several human cancer cell lines.